Hyperbaric Oxygen therapy (HBOT) is of interest to basic biomedical researchers and to practitioners of complementary and alternative medicine (CAM). HBOT is applied to a wide variety of diseases with symptoms caused by a lack of oxygen in the target tissues. It is not accepted as a treatment by the US medical community due to the lack of understanding of the underlying physiology and yet to be carefully evaluated potential dangers. Extensive pre-clinical studies are required to overcome the current bias towards HBOT and to determine its limitations. The central goal of this proposal is to understand the mechanisms of beneficial effects of HBOT and to identify its potential dangers. We recently established the critical role of the hypoxia-driven and A2A and A2B adenosine receptor (A2AR/A2BR)-mediated pathway in inhibition of overactive inflammatory cells and protection of normal tissues in hypoxic inflamed areas. We hypothesize that the elimination of this mechanism by oxygen during HBOT may explain the beneficial effects of HBOT in clearing infections by "de-inhibited" immunocytes. We are also concerned that the weakening of this protective mechanism by HBOT may lead to an unintended exacerbation of inflammatory tissue damage. We plan to test our hypothesis in studies of HBOT-treated wild type mice and of unique mice with total and tissue-specific deletion of A2AR and/or A2BR genes in different models of lung inflammation. Our specific aims #1 and 2 are to test whether HBOT exacerbates lung inflammation in studies of inhalative and intravenously induced models of lung injury in mice, while in Aim #3 we will test whether compensatory treatment with A2AR agonist will prevent the inflammatory lung injury exacerbation by HBOT in order to gain potential benefits of HBOT for other indications in CAM and other therapies. [unreadable]